Study to Assess Safety, Tolerability, Pharmacokinetics and Antitumor Activity of AZD4573 in Relapsed/Refractory Haematological Malignancies

NCT03263637 | Completed Phase 1

• 1 other identifier: D8230C00001
• Study Type: interventional
• Target: 44
• Locations: 3 countries
• Sites: 12

Brief Summary

The purpose of this study is to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of AZD4573 in subjects with relapsed or refractory haematological malignancies.

Conditions

Relapsed or Refractory Haematological Malignancies Including; Acute Myeloid Leukemia; Acute Lymphocytic Leukemia; Chronic Lymphocytic Leukemia; High Risk Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Richter's Syndrome; B-cell Non-Hodgkin Lymphoma; T-cell Non-Hodgkin Lymphoma; Small Lymphocytic Lymphoma; Multiple Myeloma

Keywords

Relapsed or refractory haematological malignancies; AZD4573; CDK9i; Acute Myeloid Leukemia (AML); Acute Lymphocytic Leukemia (ALL); Chronic lymphocytic Leukemia (CLL); High risk Myelodysplastic syndrome (MDS); Chronic Myelomonocytic Leukemia (CML); Richter's syndrome; B-cell Non-Hodgkin Lymphoma (B-cell NHL); T-cell Non-Hodgkin Lymphoma (T-cell NHL); Small lymphocytic Lymphoma (SLL); Multiple Myeloma (MM)

Outcome Measures

Primary Outcomes (3)

• Incidence of adverse events

  Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms (ECGs), safety and laboratory parameters

  At every treatment and follow up visit from the time of informed consent up to 8 months initially or if clinical benefit continues, until disease progression. Expected to be for 12 months

• Dose limiting toxicities

  DLTs will be determined from monitoring adverse events (AEs), and abnormal laboratory tests (clinical chemistry, hematology, and urinalysis), physical examinations, vital signs (blood pressure and pulse), and electrocardiogram (ECG).

  From day 1 of first cycle for a period of 8 weeks for cohorts 1 and 2, and for a period of 4 weeks for cohort 3 and for any other subsequent cohort that may be opened

• Maximum tolerated dose

  After completion of dose limiting toxicity (DLT) period (8/4 weeks) for the maximum dose cohort

Secondary Outcomes (9)

• Maximum observed plasma concentration of AZD4573

  For Cohorts 1 and 2: Over 8 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1). For Cohort 3: Over 4 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1)

• Area under the concentration-time curve for plasma concentrations of AZD4573

  For Cohorts 1 and 2: Over 8 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1). For Cohort 3: Over 4 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1).

• Volume of distribution (Vd).

  For Cohorts 1 and 2: Over 8 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1). For Cohort 3: Over 4 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1).

• Clearance (CL).

  For Cohorts 1 and 2: Over 8 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1). For Cohort 3: Over 4 weeks (from dosing Day 1 of ramp-up Cycle A until Day 1 of the target dose Cycle 1).

• Antitumor activity of AZD4573 in patients by assessing overall response rate (ORR).

  From time of first dose until discontinuation of AZD4573 expected to be for up to 12 months

Study Arms (2)

Arm A: (Cohort 1-3)

EXPERIMENTAL

dose level 1-3 in subjects with relapsed or refractory haematological malignancies excluding AML/ALL/high-risk MDS/CMML/CLL.

Drug: AZD4573

Arm B: (Cohort 1-3)

EXPERIMENTAL

dose level 1-3 in subjects with relapsed or refractory AML, ALL, high-risk MDS, CMML, CLL and Richter's syndrome.

Drug: AZD4573

Interventions

AZD4573 DRUG

AZD4573 will be administered as a intravenous (IV) infusion.

Arm A: (Cohort 1-3); Arm B: (Cohort 1-3)

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with histologically confirmed, relapsed or refractory haematological malignancies. Patients will include but are not limited to the following: Arm A : B-cell Non-Hodgkin lymphoma , T-cell Non-Hodgkin lymphoma , Small lymphocytic lymphoma (SLL) , Multiple myeloma (MM) Arm B: CLL (chronic lymphocytic leukaemia), Richter's syndrome , AML/secondary AML, ALL , High-risk myelodysplastic syndrome (MDS), CMML (chronic myelomonocytic leukemia)
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
• Must have received at least 2 prior lines of therapy
• Documented active disease requiring treatment per respective NCCN/ESMO guideline that is relapsed or refractory defined as: Recurrence of disease after response to prior line(s) of therapy Or progressive disease after completion of the treatment regimen preceding entry into the study
• Adequate hematologic, hepatic and renal function
• Women should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test before start of dosing if of child-bearing potential or must have evidence of nonchildbearing potential
• Men should be willing to use barrier contraception (ie, condoms) and refrain from sperm donation during and after the conduct of the trial.

You may not qualify if:

• Treatment with any of the following: any other chemotherapy, immunotherapy or anticancer agents within 2 weeks, any hematopoietic growth factors (e.g., filgrastim; \[G-CSF\] or sargramostin \[GM-CSF\]) within 7 days of the first dose of investigational product or pegylated G-CSF (pegfilgrastim) or darbepoetin within 14 days, any full-dose level anti-coagulation treatment sufficiently prior to treatment that INR is \<1.5 (DVT/PE prophylaxis dose is allowed) or Major surgery (excluding placement of vascular access) within 4 weeks (with regard to the first dose of study treatment on this protocol).
• With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment.
• Presence of, or history of, CNS lymphoma, leptomeningeal disease or spinal cord compression.
• History of prior nonhematologic malignancy with exceptions mentioned in protocol
• Patients with any of the following: evidence of severe or uncontrolled systemic disease, asecretory myeloma, a known history of infection with human immunodeficiency virus (HIV), serological evidence of active Hepatitis B infection, cardiac abnormalities as mentioned in the protocol, previous allogeneic bone marrow transplant, adrenal gland insufficiency or pancreatitis.
• History of severe allergic or anaphylactic reactions to BH3 mimetics or history of hypersensitivity to active or inactive excipients of AZD4573.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (12)

Research Site

Aachen, 52074, Germany

Location

Research Site

Bonn, 53127, Germany

Location

Research Site

Göttingen, 37075, Germany

Location

Research Site

Heidelberg, 69120, Germany

Location

Research Site

Ulm, 89081, Germany

Location

Research Site

Amsterdam, 1105 AZ, Netherlands

Location

Research Site

Nieuwegein, 3435 CM, Netherlands

Location

Research Site

Cardiff, CF14 4XW, United Kingdom

Location

Research Site

Manchester, M20 4BX, United Kingdom

Location

Research Site

Plymouth, PL6 8DH, United Kingdom

Location

Research Site

Southampton, S016 6YD, United Kingdom

Location

Research Site

Sutton, SM2 5PT, United Kingdom

Location

Related Publications (1)

• Cidado J, Boiko S, Proia T, Ferguson D, Criscione SW, San Martin M, Pop-Damkov P, Su N, Roamio Franklin VN, Sekhar Reddy Chilamakuri C, D'Santos CS, Shao W, Saeh JC, Koch R, Weinstock DM, Zinda M, Fawell SE, Drew L. AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells. Clin Cancer Res. 2020 Feb 15;26(4):922-934. doi: 10.1158/1078-0432.CCR-19-1853. Epub 2019 Nov 7.

  PMID: 31699827 DERIVED

MeSH Terms

Conditions

Recurrence; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelomonocytic, Chronic; Lymphoma, B-Cell; Lymphoma, T-Cell; Multiple Myeloma

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Chronic Disease; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This study is a multicentre, open-label, first in human, non-randomized, dose-escalation study including an intra-subject ramp-up. The study will consist of two, parallel dose escalation arms

Study Record Dates

• First Submitted: August 11, 2017
• First Posted: August 28, 2017
• Study Start: October 24, 2017
• Primary Completion: September 30, 2021
• Study Completion: September 30, 2021
• Last Updated: October 22, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

DE (5); NL (2); GB (5)